Process for preparing nitrooxyderivatives of naproxen

ABSTRACT

The present invention refers to a process for preparing a compound of general formula (A), as reported in the description, wherein R is a radical of naproxen or bromonaproxen and R 1 –R 12  are hydrogen or alkyl groups, m, n, o, q, r and s are each independently an integer from 0 to 6, and p is 0 or 1, and and X is O, S, SO, SO 2 , NR 13  or PR13 or an aryl, heteroaryl group, said process comprising reacting a compound of formula (B)
 
R—COOZ  (B)
 
wherein R is as defined above and Z is hydrogen or a cation selected from: Li+, Na+, K+, Ca++, Mg++, tetralkylammonium, tetralkylphosphonium, with a compound of formula (C), as reported in the description, wherein R1–R12 and m, n, o, p, q, r, s are as defined above and Y is a suitable leaving group.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a National Stage entry of International ApplicationNo. PCT/EP2003/008698, filed Aug. 6, 2003, the entire specification andclaims of which are incorporated herewith by reference.

The present invention relates to a process for preparingnitrooxyalkylesters of naproxen (2-(S)-(6-methoxy-2-naphtyl)-propanoicacid) or bromonaproxen (2-(S)-(5-bromo-6-methoxy-2-naphtyl)-propanoicacid) (Tetrahedron 1989, Vol 45, pages 4243–4252).

It is well known in the prior art that the anti-inflammatory activity of(2-(S)-(6-methoxy-2-naphtyl)-propanoic acid) is due to the S enantiomerwhich is the product in the market (Naproxen).

WO 01/10814 discloses a process for preparing the nitroxybutylester ofthe 2-(S)-(6-methoxy-2-naphtyl)-propionic acid by reacting the(2-(S)-(6-methoxy-2-naphtyl)-propionyl chloride with4-nitrooxybutan-1-ol in methylene chloride and in presence of potassiumcarbonate. The obtained ester has an enantiomeric excess (e.e.) higherthan or equal to 97%. This method has the disadvantage that severalby-products are formed, being in fact very difficult to obtainnitrooxyalkyl alcohols in pure form and 2-arylpropanoyl halides of highchemical and enantiomerical purity. Moreover, for example4-nitrooxybutan-1-ol is stable only in solution and it cannot beisolated as a pure substance.

The present invention provides a new process for preparingnitrooxyalkylesters of naproxen or bromonaproxen having an enantiomericexcess as high as that of the starting naproxen or bromonaproxen whereinimpurities and by-products are present in an essentially negligibleamount. Therefore, starting from enantiomerically pure Naproxen,enantiomerically pure esters are obtained. This is of particularimportance because: i) most of the nitrooxyalkyl esters of Naproxen arelow melting point or liquid substances, consequently the e.e. of theobtained crude esters cannot be enhanced by conventional physicalmethods ii) the absence of functional groups, apart from the ester one,in the molecules under consideration makes the purification problematic.

Another advantage of the present invention is that the startingcompounds are stable. The process of the present invention uses asstarting material a salt of Naproxen and a nitrooxy alkyl derivativehaving a leaving group, as substituent, in the alkyl chain.

Naproxen salt is used as ammonium or alkaline metals salt. The sodiumsalt is chemically and enantiomerically stable and, and is commerciallyavailable instead of 2-(S)-(6-methoxy-2-naphtyl)-propanoyl chloride(Naproxen chloride),is not commercially available in large scale, ischemically unstable and easy to racemize.

Also the nitrooxy alkyl derivative are more stable in comparison to thecorresponding nitrooxyalkyl alcohol. Therefore both reagents involved inthe present process, are by far more stable in comparison to thosereported in the prior art.

The observed high selectivity of the process was unexpected, because ofthe presence of two substituents on the nitrooxy alkyl derivative, thenitrooxy and the leaving group, which were expected to compete in thedisplacement reaction by the Naproxen salt with concomitant loss ofprocess selectivity. Another advantage of the present invention is thatthe starting compounds are stable. The process of the present inventionuses as starting material naproxen salt, instead of the acid chloride ofthe prior art process, in particular the sodium salt which is a stableand commercially available product.

Bromonaproxen nitroxooyakylesters are per se biologically active and canbe converted into the corresponding naproxen esters by conventionalmethod.

The present invention relates to a process for preparing a compound ofgeneral formula (A)

wherein:

-   R is

in which R′ is a hydrogen atom or Br

-   R₁–R₁₂ are the same or different and independently are hydrogen,    straight or branched C₁–C₆ alkyl, optionally substituted with aryl;-   m, n, o, q, r and s are each independently an integer from 0 to 6,    and p is 0 or 1, and-   X is O, S, SO, SO₂, NR₁₃ or PR₁₃, in which R₁₃ is hydrogen, C₁–C₆    alkyl, or X is selected from the group consisting of:    -   cycloalkylene with 5 to 7 carbon atoms into cycloalkylene ring,        the ring being eventually substituted with side chains T,        wherein T is straight or branched alkyl with from 1 to 10 carbon        atoms, preferably CH₃;    -   arylene, optionally substituted with one or more halogen atoms,        straight or branched alkyl groups containing from 1 to 4 carbon        atoms, or a straight or branched C₁–C₃ perfluoroalkyl;    -   a 5 or 6 member saturated, unsaturated, or aromatic heterocyclic        ring selected from

wherein the bonds, when they have an undefined position, are intended tobe in any possible position in the ring; said process comprising

-   i) reacting a compound of formula (B)    R—COOZ  (B)    wherein R is as above defined and Z is hydrogen or a cation selected    from:-   Li+, Na+, K+, Ca++, Mg++, ammonium, trialkylammonium    tetralkylammonium and tetralkylphosphonium;-   with a compound of the following formula (C)

wherein R1–R₁₂ and m, n, o, p, q, r, s are as defined above and Y isselected from

-   -   a halogen atom    -   —BF₄, —SbF₆, FSO₃—, ClO₄—, R_(A)SO₃—, in which R_(A) is a        straight or branched C₁–C₆ alkyl, optionally substituted with        one or more halogen atoms, or a C₁–C₆ alkylaryl;    -   R_(B)COO⁻, wherein R_(B) is straight or branched C₁–C₆ alkyl,        aryl, optionally substituted with one or more halogen atoms or        NO₂ groups, C₄–C₁₀ heteroaryl and containing one or more        heteroatoms, which are the same or different, selected from        nitrogen, oxygen sulfur or phosphorus;    -   aryloxy optionally substituted with one or more halogen atoms or        NO₂ groups, or heteroaryloxy and

-   ii) optionally converting a compound of formula (A) wherein R′ is Br    into a compound of formula (A) wherein R′ is hydrogen.

Preferably the present invention relates to a process for preparing acompound of formula A as above defined wherein: the substituents R₁–R₁₂are the same or different and independently are hydrogen or straight orbranched C₁–C₃ alkyl,

-   m, n, o, p, q, r and s are as defined above,-   X is O, S or

Most preferably the invention relates to process for preparing acompound of formula A according to claim 1 or 2 wherein R₁–R₄ and R₇–R₁₀are hydrogens, m, n, q, r, are 1, o and s are 0, p is 0 or 1, and X is Oor S.

In the compounds of formula (C), preferably Y is selected from the groupconsisting of Br, Cl, I, —BF₄, ClO₄ ⁻, —SbF₆, FSO₃—, CF₃SO₃—, C₂F₅SO₃—,C₃F₇SO₃—, C₄F₉SO₃—, p-CH₃C₆H₄SO₃—.

The reaction between a compound of formula (B) and a compound of formula(C) may be carried out in an organic solvent selected from acetone,tetrahydrofurane, dimethylformamide, N-methylpyrrolidone, sulfolane andacetonitrile.

Alternatively the reaction may be carried out in a biphasic systemcomprising an aprotic dipolar solvent selected from toluene,chlorobenzene, nitrobenzene, tert-butyl-methylether and a water solutionwherein the organic solution contains (C) and the water solution containan alkaline metal salt of (B), in presence of a phase transfer catalystsuch as onium salts, for example tetralkylammonium andtetralkylphosphonium salts.

The reaction is carried out at a temperature ranging from 0° C. to 100°C. and at a (B)/(C) molar ratio of 2–0.5.

The carboxylic acid salt may be prepared separately or can be generated“in situ”, for example performing the reaction between (B) and (C) inthe presence of a stoichiometric amount of a tertiary amine, oremploying an amount in excess of said amine.

The compounds of formula (C),may be prepared by nitrating compounds offormula (D) reported here below, with nitrating agents selected forexample, sulfonitric mixture and the like:

wherein M is OH, and

-   Y, X, m, n, o, p, q, r, s and R₁R₁₂, have the meanings mentioned    above.

Alternatively the compounds of formula (C) may be obtained by reacting acompound of formula (E) with nitrating agents selected for example fromalkaline metal nitrates, quaternary ammonium nitrates, quaternaryphosphonium salts and AgNO₃, Zn(NO)₂.6H₂O:

wherein:

-   Y, X, m, n, o, p, q, r, s and R₁–R₁₂, have the meanings mentioned    above.

Alternatively the compounds of formula (C) may be obtained by reacting acompound of formula (F)

wherein W is OH or halogen, with a compound selected from alkyl and arylsulfonylchloride, trifluoromethansulfonic acid anhydride, when W is OHor AgSbF₆, AgBF₄, AgClO₄, CF₃SO₃Ag, AgSO₃CH₃, CH₃C₆H₄SO₃Ag when W ishalogen.

Nitration of compound (D) was performed in an organic solvent, generallyin a solvent selected from acetone, tetrahydrofurane, dimethylformamide,N-methylpyrrolidone, sulfolane, acetonitrile, methylene chloride etc.,with nitrating agents selected from transition metal salts or, when M isOH, with nitrating systems based on nitric acid, such as the sulfonitricmixture.

The (D)/nitrating agent molar ratio is of from 2 to 0.5, in particularof 1.5 to 0.5 and the nitration is carried at a temperature ranging from0° C. to 100° C., preferably from 15° C. to 80° C.

The reaction product (C) may be isolated or its solution can be employedas such for the reaction with substrate (B) to give (A).

Nitration of compound (E) may be carried out in an organic solvent,generally in a solvent selected from acetone, tetrahydrofurane,dimethylformamide, N-methylpyrrolidone, sulfolane, acetonitrile,methylene chloride etc., with nucleophilic nitrating agents such asalkaline metal nitrates, onium salt nitrates, for exampletetraalkylammonium, tetraalkyl-phosphonium or trialkylammonium nitrateand so on.

The reaction is carried out at a temperature of from 0° C. to 100° C.,in particular of 15° C. to 80° C. and at a molar ratio (E)/nitratingagent of from 20 to 2, preferably of 8 to 1.

The reaction product (C) may be isolated or its solution can be employedsuch as in the reaction with substrate (B) to give (A).

The reaction for obtaining compound (C) from (F) may be carried out inan organic solvent, generally selected from the group consisting ofacetone, tetrahydrofurane, dimethylformamide, N-methylpyrrolidone,sulfolane, acetonitrile, methylene chloride and the like, with atransition metals salts selected from those of silver, zinc, mercury or,when W is OH, the reaction was performed with an acid chloride such asmethanesulfonyl chloride etc., or with a suitable anhydride such astrifluoro-methanesulfonic anhydride.

The reaction was performed at a temperature ranging from −20° C. to 100°C., in particular from −20° to 60° C. at a molar ratio compound(F)/reagent of from 2 to 0.5, preferably of 1.5 to 0.5.

The reaction product (C) may be isolated or its solution can be employedas such in the reaction with substrate (B) to give (A).

EXAMPLES Preparation of 4-nitrooxybutyl bromide According to Chem.Pharm. Bull., 1993,41,1040

Nitric acid (90%, 0.8 mol) was dropped under stirring in sulfuric acidmaintained at 0° C. (0.8 mol) and the mixture was then stirred at 0° C.for 80 minutes. In the solution thus obtained and maintained at 0° C.,under stirring 4-bromobutanol was dropped (0.4 mol) and the mixture wasstirred again for additional 210 minutes at the same temperature. Thesolution was then poured in a water-ice mixture and extracted twice withdiethyl ether. The ether extracts were combined together and washed witha sodium bicarbonate saturated solution. The solvent was evaporated offunder vacuum to give a yellow oil (yield: 84.8%).

Example 1 Preparation of 4-nitrooxybutyl p-toluenesulfonate

To a solution of 4-bromobutanol (5.0 g, 33 mmol) in pyridine (50 ml)kept at 0° C., under stirring and under nitrogen atmosphere tosylchloride (6.8 g, 36 mmol) was added. The resulting solution was keptunder stirring for further 20 minutes and then stored overnight at −18°C. The reaction mixture was poured in a water/ice mixture (about 400 ml)and extracted with ethyl ether (500 ml). The organic phase was washedwith 6N hydrochloric acid (500 ml) and dried on sodium sulfate.Evaporation of the solvent under vacuum, provided an oily residue (7 g).To a solution of the oily residue (7 g, 23 mmol) in acetonitrile (50ml), kept under stirring and under nitrogen at room temperature, silvernitrate (7.8 g, 46 mmol) was added. After nearly 15 minutes, theformation of a yellow, insoluble product was observed. The heterogeneousmixture was kept under stirring overnight. The insoluble was removed byfiltration and the solution was poured in water (200 ml) and extractedwith ethyl ether (2×250 ml). The combined organic extracts were driedover sodium sulfate. Evaporation of the solvent under vacuum afforded anoily residue (5 g).

Chromatography of the residue on silica gel (100 g), with hexane/ethylether mixture as eluent, gives the title product (3 g), m.p. 38–40° C.and a purity, determined by HPLC, higher than 98%,.

FTIR (solid KBr, cm-1): 2966, 1626, 1355, 1281, 1177, 1097, 959, 876,815, 663, 553.

300 MHz 1H NMR (CDCl3) delta 1.77 (m, 4H); 2.35 (s, 3H); 4.06 (m, 2H);4.38 (m, 2H); 7.36 (2H); 7.7 (2H).

Example 2 Synthesis 2-(S)-(6-methoxy-2-naphthyl)propanoic acid,4-(nitrooxy)butyl ester

KHCO₃ (5.22 g, 52 mmol) was added under nitrogen to a solution of2-(S)-(6-methoxy-2-naphthyl)propanoic acid (Naproxen) (99 e.e.determined by chiral HPLC) (10.0 g, 43 mmol) in DMF (200 ml).

The heterogeneous mixture was heated up to 50–60° C. and kept at thistemperature under nitrogen and under magnetic stirring for 90 min. Thereaction mixture was allowed to cool down to room temperature. Potassiumiodide (2.14 g, 12.9 mmol) and 4-bromobutylnitrate (14.48 g 73 mmol)were added to the above mixture, and the reaction mixture was stirred atroom temperature under nitrogen for 25 h. Water (200 ml) was addeddropwise in 5 min. to the reaction mixture. The mixture was extractedwith t-BuOMe (200 ml), the organic phase was washed with NaCl 10%aqueous solution (2×200 ml) and was dried over Na₂SO₄ Evaporation of thesolvent in vacuo provided an oily residue (17.3 g). Chromatography onsilica gel (eluent hexanes/ethyl acetate) of the residue provided2-(S)-(6-methoxy-2-naphthyl)propanoic acid,4-(nitrooxy)butyl ester as anyellow oily compound (10.8 g, 73% yield, e.e., determined by HPLC,higher than 99%).

The product was identified by comparison with an authentic sample.

Example 3 Synthesis 2-(S)-(6-methoxy-2-naphthyl)propanoic acid,4-(nitrooxy)butyl ester

KHCO₃ (5.22 g, 52 mmol) was added under nitrogen to a solution of2-(S)-(6-methoxy-2-naphthyl)propanoic acid (Naproxen) (99 e.e.determined by chiral HPLC) (10.0 g, 43 mmol) in DMF (200 ml).

The heterogeneous mixture was heated up to 50–60° C. and kept at thistemperature under nitrogen and under magnetic stirring for 90 min. Thereaction mixture was allowed to cool down to room temperature.4-(nitrooxy)butyl-4-methylbenzenesulphonate (21.1 g 73 mmol) was addedto the above mixture, and the reaction mixture was stirred at roomtemperature under nitrogen for 25 h. Usual aqueos work up followed bychromatography on silica gel (eluent hexanes/ethyl acetate) of thereaction crude provided 2-(S)-(6-methoxy-2-naphthyl)propanoicacid,4-(nitrooxy)butyl ester (10.4 g, 70% yield, e.e., determined byHPLC, higher than 99%).

Example 4 Synthesis 2-(S)-(+)-(5-bromo-6-methoxy-2-naphthyl)propanoicacid, 4-(nitrooxy)butyl ester

A mixture of triethylamine (5.25 g, 52 mmol), of2-(S)-(5-bromo-6-methoxy-2-naphthyl)propanoic acid (Bromo-Naproxen)(13.3 g, 43 mmol); e.e.99%) and of 4-bromobutylnitrate (43 mmol) in DMF(120 ml) was stirred under nitrogen for 2 days at 25° C.

Removal of DMF under vacuum followed by usual aqueous work up providedthe reaction crude. Chromatography on silica gel (eluent hexanes/ethylacetate) of the residue provided pure2-(S)-(5-bromo-6-methoxy-2-naphthyl)propanoic acid,(nitrooxy)butyl ester(11.9 g; 65% yield; e.e., determined by HPLC, higher than 99%).

The product was identified by spectroscopic methods.

1. A process for preparing a compound of general formula (A)

wherein: R is

 in which R′ is a hydrogen atom or Br R₁–R₁₂ are the same or differentand independently are hydrogen, straight or branched C₁–C₆ alkyl,optionally substituted with aryl; m, n, o, q, r and s are eachindependently an integer from 0 to 6, and p is 0 or 1, and X is O, S,SO, SO₂, NR₁₃ or PR₁₃, in which R₁₃ is hydrogen, C₁–C₆ alkyl, or X isselected from the group consisting of: cycloalkylene with 5 to 7 carbonatoms into cycloalkylene ring, the ring being eventually substitutedwith side chains T, wherein T is straight or branched alkyl with from 1to 10 carbon atoms; arylene, optionally substituted with one or morehalogen atoms, straight or branched alkyl groups containing from 1 to 4carbon atoms, or a straight or branched C₁–C₃ perfluoroalkyl; a 5 or 6member saturated, unsaturated, or aromatic heterocyclic ring selectedfrom

said process comprising: i) reacting a compound of formula (B)R—COOZ  (B) wherein R is as above defined and Z is hydrogen or a cationselected from Li+, Na+, Ca++, Mg++, tetralkylammonium,tetralkylphosphonium, with a compound of formula (C)

wherein R₁–R₁₂ and m, n, o, p, q, r, s are as defined above and Y isselected from a halogen atom —BF₄, —SbF₆, FSO₃—, R_(A)SO₃—, in whichR_(A) is a straight or branched C₁–C₆ alkyl, optionally substituted withone or more halogen atoms, or a C1–C6 alkylaryl; R_(B)COO⁻, whereinR_(B) is straight or branched C₁–C₆ alkyl, aryl, optionally substitutedwith one or more halogen atoms or NO₂ groups, C₄–C₁₀ heteroaryl andcontaining one or more heteroatoms, which are the same or different,selected from nitrogen, oxygen sulfur or phosphorus; aryloxy optionallysubstituted with one or more halogen atoms or NO₂ groups, orheteroaryloxy and ii) optionally converting a compound of formula (A)wherein R′ is Br in a compound of formula (A) wherein R′ is hydrogen. 2.A process for preparing a compound of formula A according to claim 1wherein: the substituents R₁–R₁₂ are the same or different andindependently are hydrogen or straight or branched C₁–C₃ alkyl, m, n, o,p, q, r and s are as defined above, X is O, S or


3. A process for preparing a compound of formula A according to claim 1wherein R₁–R₄ and R₇–R₁₀ are hydrogens, m, n, q, r, are 1, o and s are0, p is 0 or 1, and X is O or S.
 4. A process for preparing a compoundof formula A according to claim 1 wherein Y is selected from the groupconsisting of Br, Cl, I, —BF₄, —SbF₆, FSO₃—, ClO₄, CF₃SO₃—, C₂F₅SO₃—,C₃F₇SO₃—, C₄F₉SO₃—, p-CH₃C₆H₄SO₃—.
 5. A process for preparing a compoundof formula A according to claim 1 wherein the reaction is performed inan organic solvent selected from acetone, tetrahydrofurane,dimethylformamide, N-methylpyrrolidone, sulfolane and acetonitrile.
 6. Aprocess for preparing a compound of formula A according to claim 1wherein the reaction is performed in a biphasic system comprising anaprotic dipolar solvent selected from toluene, chlorobenzene,nitrobenzene, tert-butylmethylether and a water solution wherein theorganic solution contains (C) and the water solution contain an alkalinemetal salt of (B), in presence of a phase transfer catalyst.
 7. Aprocess for preparing a compound of formula A according to claim 1wherein the reaction is performed at a temperature ranging from 0° C. to100° C.
 8. A process for preparing a compound of formula A according toclaim 1 wherein the compounds of formula B and C are reacted at a(B)/(C) molar ratio of 2–0.5. 9.2-(S)-(5-bromo-6-methoxy-2-naphthyl)propanoic acid,4-(nitrooxy)butylester.